Therapeutically valuable derivative of sulfones



Patented Sept; 7, 1943 THERAPEUTICAILY V OF S ALUABLE DERIVATIVE ULFONES Max Dohm and Walter 's clioeller, Berlin- Charlottenbur -Otto Albert Alhard Laubereau, Berlin-Nenkolln, Hermann Fox, Berlin-Prohnau, Erich Leckzyck, Berlin-Halensee, and

Hans Herloi'l Inhoflen, Berlin-Wilmersdorf,- Germany, assignors to Schering Co p r t on, Bloomfield, N. 1.; a corporation of New Jersey No Drawing. Application May 11, 1940, Serial No. 335,868. In Germany May 27, 1939 1 Claim. (Cl. 260-3916)" This invention relates to derivatives of sulfones and more particularly to therapeutically valuable sulfones and a method of making the same.

A particularly eflective agents against infections caused, for example, by cocci, such as gonocccci, streptococci and the like, there have proved derivatives ct sulfones, as for instance, diphenylsulfones, being substituted in 4,4' -position by nitroor amino groups; these effects, however, are connected with a high toxicity. And'this is the reason, why these derivatives of sulfones-do not have'therapeutical value. Thus, for instance, in mice tests the 4,4-diamino diphenyl sulfone is about 100 times more eiiective against streptococci than the sulfanilio acid amide but at the same time 25, times as toxic as the latter (compare, for instance, Lancet, vol. 232,.page 1332) Now, it has been iound; that other derivatives of suliones may be produced which are consider-- ably free from poisonous efi'ects without showing decreased effectiveness. These suliones correspond to the general f rmu a:

In this formula there represent:

R and Rf: aromatic and/or heterocyclic radicals,

Y: hydrogen, a hydrocarbon or acyl radical,

which may also be substituted by OR"' or NHY',

or the COXegroup,

X: the groups NHY' or X: the group OR" or NHY', 'R": a hydrocarbon radical,

Y: hydrogen, a hydrocarbon radical, which may be substituted, for instance, by '-COOH and are preformed and the residues NH.CO.X- or -CO.X are introduced, or

(2) By those, in which the NH.C0.X group is already contained in the molecule or in parts of the same, while the sulfone group is to be produced.

The methods, for producing these new sulfones, as described under (1) are known per se and are used, for example, in the manufacture of Dulcin, a urea derivative of phenetidine (see, for instance, Apothekerzeitunz, vol. 9 (1894) page 200 11.; Journal flir praktische Chemie (2) vol. 30

' (1884), page 103 and the German Patents Tics.

63,485, 76,596, 77,420 and 79,718) Y The preferably applied methodconsists in reacting suifones' of the general formula znsozrtnz' wherein R and. R indicate aromatic and/or heterocyclic radicals, while Z represents a free out with phosgene so as to yield a compound of the general formula Z.R.SO2.R'.NH.CO.C1, into the carbalkoxy amino compounds, or by reaction with ammonia or agents, capable of yielding ammonia, such as ammonium carbonate and the like, or amino compounds, such as amino acid, amino pyridine and others into the corresponding urea compounds. Hereafter, if necessary, Z

-may be transformed into-the free amino group. .-'Ihis com'erslQn, for instance", by means of re-.

duction or reductive splitting 33, or by treatment with ammonia or sodium amide, or by saponiflcation, has to be carried out so carefully, that a splitting oil of the COX-group formed before does not take place.

The manufacture ,of these new sulfones is also possible by directly reacting the sulfones of the above general formula Z.R.SO2.R'.Z' with an alkalicyanate, suitably in the presence of glacial acetic acid, or with a urea halogenide, for in-= stance, urea chloride, or even with urea, its salts or monoacyl derivatives, suitably by heating, whereupon Z is converted into the amino group, it need be.

The second method consists, for instance, in converting compounds, already containing a NHCOX group, into suliones. For this purpose already known methods may be used, such as are described among others in Houben "Die Methoden der organischen Chemie, 3rd edition, vol. 3, page 1278 ft. According to these methods sulfides of the formula X.OC.HN.R'.S.R.NYY" as they are obtainable, for instance, by reacting mercapto compounds of the general formula known oxidation agents.

X.OC.HN.R'.SO.Me, where R and x have the above given meaning while Me'indicates a metal, especially an alkali metal, such as the sodium compound'of a thiophenol urea, with oompound of the formula Hal.R.Z" wherein R also has the above given' meaning while Z"- represents a group conv'ertible into the aminogroup, may be oxidized to sulfones whereby also the intermediately formed corresponding sulfoxydes of the formula. X.OC.HN.R.SO.R.N.YY" may be used as starting material. As oxidizing agents there may be employed potassium permanganate chromium trioxide, hydrogen peroxide' or other Subsequently, if necessary, the amino group or the group NYY" may be reformed in the place of Z-position.

Furthermore, according to this second principal way of procedure, salts of sulfinic acids of'the general formula X.OC.HN.R.SG2;M, wherein R,-X and Me have the above mentioned meaning, may be condensed to sulfones with compounds of the formula HalR'Z", wherein R also has the above mentioned meaning. while Z" represents a group, capable'of activating a halogen atom and being convertible into the amino group, especially a nitro group (see applications .Serial Nos. 237,926 and 371,412, corresponding"Ger man-applic. Sch. 119,715 Ive/12 After the condensation Z" may be transformed into the amino group or the group NY if need be. Instead of the salts of sulfinic acid also suliinic acids of the formula X.OC.HN.R.SO2I-I, wherein R and X have the above given meaning, or their amides may be reacted with amino compounds of the aromatic or heterocycl c series, suitably in mentionedsuliinic acids may be reacted withamino compounds of the formula RNYY", the amino group of which is suitably protected, for instance, by acylation (see application Ser. No.

tioned under (1) carbalkoxy or urea sul'fones are obtained from sulfones of the formula .-'-also from sulfides" or sulfoxides oi the for- .Derivatives"ofsulfonesfprepared according to 314,512). With especially hi h yield'the new sulfones may be obtained hv condensation of compounds of the formula X.QC.HN.R'.SO2,Hal with compounds of the formula RNYY", wherein R, R. X and Y" have the above shown meaning while Y represents an alkyl. especially a methyl radical, or an acyl radical, capable '01" being readily split off such as amactyl radical or the like. said' condensation preferably being carried out in the presence. of aluminum [chidride. The condensation p oduct is then subjected, if required. to partial saponification'in order to split oif'the acvl group. The condensation in the presence of alum num chloride may than.

this inVentiQn may be converted in the same manner, as described, for instance, in application Ser. No.367,224 (appln. corresponding to German appln. NolScli. 119,519 IVd/22a) into azo compounds, capable of forming water-soluble salts, said azo compounds corresponding to the general formula AZ.R.SO2.R.NH.CO.X, wherein R, R and X have the above given meaning, while Az indicates an azo group with an aromatic or heterocyclic radical, containing at least one, but preferabiyrseveral groups, capable of forming water-soluble salts. These sulfone derivatives may be used forinjections on account of their solubility in water.

The following examples serve to illustrate the invention without, however, limiting the same to '4 Errdmpie 1 ed with cold water, whereby a c olourless solidmass is obtained, which may be filtered off by suction. This solid fraction is washed with water, dried in a yacuum desiccator, and recrystallized from amyl alcohol. Thus, bis-(acetylamino-diphenyl sulfone)-urea is obtained melt-' "'ing at 23l+20 C. with decomposition.

This substance is heated in 18-20% hydrochloric acid for about 30 minutes to boiling,

-whereby. it is completely dissolved and trans- -HO3S.R.NYY", whereupon, in both cases, the

aminogroup may be ref rmed. I

Furthermore, to these methods there belong all those, by which.in the same manner as menformed to bis-(amino-diphenyl sulfone)-urea. This substance is recrystallized from methanol and melts at 227-228 C.

Example 2 10 grs. of 4-nitro-4-amino diphenyl sulfone (melting point 169-1'70 0.), obtained from 4- nitroi-acetyiamino diphenyl sulfone by saponification, are dissolved in 400 cos. of hot toluene and a stream of phosgene is passed into the boiling solution for about 15 minutes until saturation. Then the solutionis worked up accordingto Example 1. By recrystallisation from a mixture of equal volumes of alcohol and acetone the bis-(nitro diphenyl sulfoncleurea is obtained melting at 265 C. with decomposition. 10 jgrs. of said substance are suspended in 150 cos. -of alcohol and to this suspension there is added a mixture of 44 grs. of 'zinc chloride in cos. of alcohol, saturated with hydrogen chloride, whereby the temperature increases to about 60 G. Then, the mixture is heated for 1 hour on the water bath and is brought dryness in a desiccator. The residue is rendered strongly-alkaline by addition of a 33% sodium hydroxide so.-

lution while cooling; whereupon the mixture is extracted with acetic acid ester. ester solution is dried by means of calcium chloride and after evaporation to a small volume is mixed with p'etroi ether. On standing for several hours the bis-(amino diphenyl sulfone)-urea is filtered off by suction and recrystallized from methanol. Melting point 22'l The reduction of the nitro group may also be carried out by means of sodium hydrosulfite as well as by means of catalytically activated hydrogen.

Example 3 100 grs. of 4-nitro-4-amin'o diphenyl sulfone are dissolved, while stirring in 500 cos. of glacial acetic acid at a temperature of 90 C., whereupon the solution is cooled down to a temperature of 70 C. Then 80 grs. of calcium cyanate v are added under continuous stirring to the solution in.the course of about one hour, whereby the temperature is maintained at, about 70 C.- At the end of adding the cyanate, the solution may be heated, if necessary. After having introduced about half of the calcium cyanate a precipitatebegins to form,'which is filtered oil by suction after standing for about 20-24 hours. The filtered residue is triturated with 20% of hydrochloric acid, again filtered oil by suction,

first washed with 20% hydrochloric acid and The acetic acid Example 4 A solution of 5.6 grs. of nitro-.4-amino diphenyl sulfone and 4.8 grs. of urea in 60 cos. 'of glacial acetic acid are heated for 15 hours to 105-1 l0 C. After cooling the solution is precipitated with twice its volume of water. After standing for several hours, the precipitate formed' Example 5 5.6 grs. of 4-nitro-4-amino diphenyl sulfone are dissolved at room temperature in 25 cos. of dioxane. While excluding any moisture and avoiding any increase .of temperature phosgene is introduced into this solution. After several then with' water, and finally dried. Thus, 4-nitro-4'-ureido diphenyl sulfone of melting point 215-216 C. is obtained in a crude yield of 85 grs. On recrystallisation from about 1000 cos. of boiling glacial acetic acid 43.5 grs. of the pure product having a melting pointof 220-221 C. are isolated. The mother liquor, evaporated to dryness in vacuo, yields about 8.5 grs. of the same product, thus, giving a total yield of 52 grs. corresponding to 45.5%. 7

On catalytic hydrogenation in the presence of platinum black 4-amino-4-ureido diphenyl sulfone is obtained therefrom.

The reduction may also be carried out as follows: I

32 grs. of 4-nitro-,'-ureido diphenyl sulfone are gradually mixed while stirring with 1'70 cos. of a solution of 450 grs. of SnCl2.2H2O in 1000 cos. of glacialv acetic acid intp which dry hydro- Ben chloride gas was passed. Thereby the reaction mixture in which the temperature increases by itself is kept at a temperature below 65 C. 'I'hereupon the mixture is'stirred for two further hours at about C. The tin double salt formed after standing for several hours istransformed intothe free base by methods known per se. The 4-amino-4'-ureido-diphenyl sulfone obtained on recrystallisation from alcohol melts at 202-203" C. One may also reduce the 4-nitro-4f-ureido-diphenyl sulfone by means of anickel catalyst as follows:

64 grs. oi. the nitro compound are reduced in 1000 cos. of ethyl alcohol in the presence of 10 grs. of a nickel catalyst in a manner known per se. Thereafter about 1000 cos. of ethyl alcohol are added, the solution heated to boiling, filtered oif from'the catalyst and the filtrate concentrated by evaporation. 58 grs. of 4-amino-4,'-ureido diphenyl sulfone of melting point 200,-201 C. corresponding to a yield of 86.3% (crude pIOd'n not) are obtained in crystalline form.

76 nitro diphenyl sulfone crystallizes-and is filtered minutes.

minutes a yellow precipitate is formed, but which gradually dissolves. Afterhaving introduced phosgene into the solution for about 15 minutes,

a carbamic acid chloride crystallizes in the form of a light-yellow product. For its complete precipitation, 50 cos. of absolute ether are added to the reaction mixture. The remaining phosgene is eliminated'by passing through a stream of dry air, the precipitate is then filtered oif by suction and washed with absolute ether. By this method the carbamic acid chloride in almost quantitative yield is obtained, melting at ISO-162 C. thereby decomposing. On introducing the carbamic acid chloride into an excess of concentrated ammonia a yellow precipitate is formed, which, after standing for several hours, i filtered oil by suction and washed with water. This precipitate represents the 4-nitro-4' -ureido diphenyl sulfone, melting at 222 C; thereby decomposing. Yield: almost quantitative.

Example 6 To a solution of 5 gm. of 4,4-diamino diphenyl sulione in 60 cos. of glaoial'acetic acid 4 grs. or kaiium cyanate are added in the course of 10 After allowin the solution to stand for 24 hours, the solution i completely precipitated by water, the crystalline precipitate filtered of! by suction and rtriturated in the cold with 10% hydrochloric acid in order to remove even tually present starting material. After a further filtration, the precipitate is washed with water.

and recrystallized from 50% acetic acid. After two recry'stallizations, the 4-acetyl amino-4- ureldo diphenyl gulfone has a melting point of 254 C. (thereby decomp i By careful saponification the acetyl group may be split of! thereby producing the Corresponding amino compound. r 1

Ezrample 7 v 16 gr. of urea chloride are introduced into a of pyridine. have beenadded. During the introduction of theurea chloride, the temperature increases to 30-40" C; After allowing the reaction mixture to stand for some time the 4-ureido-4'- to 20 grs. of glycocoll ethyl ester.

off by suction, washed with water and recrystallized from 50% acetic acid. M. P. 225-226 C. Yield: 80-85%. The reduction to the l-ureido- 4'-amino diphenyl sulfone may be carried out as described in Example 3.

Example 8 0.8 gr. of the carbamic acid chloride, as obtained according to Example 5, are introduced into 12 grs. of aniline whereby reaction takes place under development of heat. The mixture finally solidifies. After standing for two hours the aniline chlorohydrate formed and the excess of aniline are removed by washing with water and dilute hydrochloric acid, the residue is dried and recrystallized from alcohol. The -nitrocarbaminyl anilido diphenyl sulfone forms yellowish prisms, which melt at 129-130" C. under lively development of gas, solidify again at 140- 160 C. and finally melt at 200 C. Yield: 0.75

Example 9 0.5 gr. or" carbamic acid chloride, as obtained according to Example 5, are introduced into a solution of 04 gr. of p-aminobenzoic acid in 6.5

cos. of dioxane whereby the temperature of the mixture slightly increases. On standing for several hours a precipitate forms, which is filtered off by suction, washed with dilute hydrochloric acid, and recrystallizedfrom alcohol. Light-yellow needles of 4-nitro-4'-( carbaminyl aminoben- .zoic acid) -diphenyl sulfone are obtained thereby which melt at 253 C. thereby decomposing, after changing colour from about 230 C. upwards. The compound is soda-soluble and is precipitated from a soda solution by acids.

Example 1 32 'grs. of crude 4- nitro-diphenyl-sulione-4'-v carbaminic acid chloride are dissolved in 420 ms; of dioxane and the clear solution is then added After the reaction is finished and after standing for several hours the solution is filtered oil by suction, the precipitate washed with water and recrystallized from glacial acetic acid. The 4-nitro-diphenylsulfone-'eureido-acetic acid ethyl ester obtained melts at 228229 C. Yield: 20 grs.

3.8 grs. of this ester are suspended in 25 cos.

I of concentrated hydrochloric acid. After addition of 6.8 grs. of SnClaZHaO in 25 cos. of concentrated hydrochloric acid, the solution is heated to aboutv 70 C. The clear solution obtained by this reaction, which lasts for about hour, is separated by filtration by' suction from the precipitate formed on standing for 12 hours, and the tin double salt filtered off is dissolved in 2% hydrochloric acid. From this solution the tin is precipitated by means of hydrogen sulfide. After filtration crystals are obtained by evaporation of the filtrate in a vacuum, which on precipitation from their solution in sodium hydroxide solution by means of acetic acid, have a melting point of 228-229 C. and represent the 4-amino diphenyl sulfone 4'=ureido acetic acid. Yield: 20 grs.

' Example 11 A solution of 115 grs. of 4-amino-4'-nitro di- 7 phenylsulfide in 600 ccs. of dioxane is added to a solution of 105 grs. of phosgene in 500 ccs. of dioxane while stirring at room temperature. Thereafter the stirring is continued for one more hour, whereupon the precipitate formed is filtered oil by suction and introduced into 750 ccs. of 25% ammonia while stirring. After standing for several hours it is again filtered off by suc= tion, the residue-washed with water and dried. Melting point 202-203 C. on recrystallisation from 50% acetic acid. Yield: 160-170 grs.

150 grs. or" the thus obtained 4-ureido-4-nitro diphenyl sulfide are dissolved in about 1 l. of hot glacial acetic acid and the solution, after adding 180 grs. of a 30% solution of hydrogen peroxide, corresponding to 3 mols, is heated on the water bath for two tothree hours. Cooled, the quite pure d-ureidolenitro diphenyl sulfone, which crystallizes, is filtered ofi by suction. M. P. 225 C. Yield:%.

The reduction of this sulione to l-ureido-Q amino diphenyl sulfone may be carried out according to Example 3.

Erample 12 28 grs. of 4-amino--nitro diphenyl sulfone are dissolved in ccs. of dioxane and 7 ccs. of pyridine. To this solution there are added drop by'drop 8 .3 ccs. of chlorocarbonic acid ethyl ester at a temperature of 40-50" C. The precipitate, formed after standing for a rather long period of time, is filtered oil by suction and washed with water, M. P. 2l4-15 0., on recrystallisation from glacial acetic acid. Yield: 24 grs. or" l-nitro-4;'- carbethoxyaminodiphenylsulfone.

The same com-pound is also obtained with a good yield on boiling 4-nitro-diphnyl-sulfone- 4-carbaminic acid chloride in alcohol for about an hour.

6.0 grs. of l-nitro-' carbethoxyaminodiphenylsulfone and 3 grs. of a nickel-catalyst in 200 ccs. of ethyl alcohol are shaken at 40-50" C. with hydrogen, until the calculated amount is absorbed. Duration of the hydrogenation: about 8 hours. The solution is filtered while hot and the residue is washed with hot alcohol. After cooling, pure 4-amino-4-carbethoxy amino diphenyl sulfone with a M. P. of 228 C. precipitates from the filtrate. Yield: 80%.

Example 13 42 grs. of '4,4'-diamino diphenyl sulione are dissolved in 20 ccs. of acetone. After addition of 17 cos. of pyridine at 0 C. 1.8 grs. of chlorotered off by suction, washed with water and several times recrystallized from alcohol.

M. P. 226-228 C. On this reaction AJ-di-(carbethoxy amino) -diphenyl sulfone is obtained as byproduct, which, owing toits low solubility in alcohol, may be easily separated from the -amino- 4'-carbethoxyainino diphenyl sulfone.

Example 14 4.2 grs. of 4-carbethoxyamino-4-ureido diphenyl sulfone, obtained in, an analogous mane ner as described in Example 12 by reacting amino ureido diphenyl sulfone instead of 4-amino-4- nitro diphenyl sulfone with chlorocarbonic acid ethyl ester, are boiled in 240 ccs. of 50% sulfuric acid for 15 minutes and then filtered while still hot.

' On cooling the sulfuric acid salt of the base crystallizes, and is filtered and converted into the free base 4-amino-4'-carbethoxyamino diphenyl sulfone. M. P. 227-228.-C., on recrystallisation from alcohol.

Example 15 1 3.5 grs. of chlorocarbonic acid ethyl ester are asaagses introduced, while'cooling by means or water, into a solution of 8.7 grs. of 4-amino-4-acetylamino diphenyl sulfone, dissolved in 25 cos. of acetone, to which 3v cos. ofpyridine'have been added.

, After finishing the reaction by slightly heating on a water bath, the 4-carbethoxyamino-4-ace7- Example 16 o 50 grs. of p-carbethoxy-aminobenzolsulfinio acid, 44 grs, of pbromo nitrobenzene and. 30 grs. of anhydrous potassium acetate in 50 cos. of methanol are heated in an autoclave up to 120-l30 C. for 5 to 6 hours while stirring all the time. The reaction product is filtered ofl by suction, extracted first with water and then with ether to remove the non-reacted bromo nitro benzene whereupon the residue is recrysta Yield: 20-25 grs. The nitro compound obtained is then subsequently reduced to 4'-carbethoxyamino-4-amino diphenyl. sulione, as described in Example 12.

' Example 17 To 26 grs. of carbethoxyaminobenzosulfonic acid chloride and 13 grs. of acetanilide suspended in carbon disuifide, there are added portion by portion 28 grs. of aluminum chloride. To wards the end of the reaction the evolution of hydrochloric acid gas is accelerated by heating on the water bath, The reaction finished, the solvent is' evaporated to a large extent either directly or in a low vacuum, the residue, while still warm, is diluted withice-water and then worked up in the usual manner.

The reaction product, p-carbethoxyamino-p'- acetyl-amino diphenyl sulfone, crystallizes from glacial acetic acid with a melting point of 244445 C. o

10.0 grs. .of this sulfone are dissolved in 50 cos.

'of formic acid and boiled with 50 cos. of concentrated hydrochloric acid. On cooling the partly saponiiied compound crystallizes from the reaction mixture, to which the same volume of water was added. The p-carbethoxyamino-p'- amino diphenyl sulfone obtained has a melting point of 229-230 C. on recrystallisation cohol. Yield: 90%,

Emample 18 v sulione obtained is then converted into the free base.

Example 19 To a solution i 5.6 grs. of 4-nitro-d-amino diphenyl sulfone in 50 cos. of pyridine there is added while stirring at l0 to -15 C. a solu-' tion of 2 grs. of phosgene in 20 cos. of pyridine made at --15 .C. After keeping the reaction mixture for 30 minutes at this low temperature and for several hours at about 0 C. it is precipid fror'nfiglacial acetic acid. M. P. 214 C.

from al- The chlorohytated by addition of a use water. Yellow needies of bis-(4-nitro diphenyl sulfone) -4-urea are obtained in a yield of 5.4 grs. which on re I crystallisation from pyridine melt at 272-274 C.

thereby decomposing.

Example 20 To a solution of 5.6 grs. of 4-nitro-4'-amino diphenyl sulione in cos. of pyridine there is added, while stirring, at 10 to l5 C. a solo. tion of 3 grs. of carbonic acid dibromide in 25 cos. of pyridine, said solution made at -l5 C. After standing for about 30 minutes at this low temperature-the temperature is gradually allowed to rise to 17-20 (3,, whereupon after standing for 10-12 hours water is added to the reaction mixture causing precipitation of N,N- bis(4-nitro diphenyl sulfone)-4-urea which forms yellow needles and melts after recrystallisation from pyridine at 27227 4 C. thereby decomposing. Yield: 5.0 grs.

Example 21 To a solution of 5.0 grs. of 4-amino-4'nitrodiphenyl sulfide in 20 cos. of dioxane with addition of 1.6 ccs..of pyridine there are added at about 40-50 C. 2.2 grs. of chioro carbonic acid ethyl ester, whereupon the reaction mixture is heated for a short time onthe steam bath and poured into a large volume of ice water. The precipitate formed, the 4-nitro-4'-carbethoxyamino diphenyl sulfide, is filtered on by suction, washed with water and recrystallized from methanol or glacial acetic acid, M. I. 132433 C. Yield: about 70%.

On oxidizing this compound with 4 mols of hydrogen peroxide 4 -nitro-d'-carbethoxy amino diphenyl suifone having a melting point of 215-216 (3., thereby decomposing, is obtained.

Example 22 A suspension of 390 gm. of 4-nitro-4'-amino diphenyl sulfide in 600 cos. of dioxane is added in small portions while stirring to a solution of 200 grs. of phosgene in 500 cos. of dioxane at a temperature of 20-25" C. Thereupon the reaction mixture is continued to be stirred for 1 hour at the same temperature, filtered off by suction, pressed in order to remove most of the adhering mother liquor, and the filtered residue introduced, while stirring, into 1.51. of 25% ammonia. Stirring is continued for about 3 further hours. After allowing the, reaction mixture to stand for several hours it is filtered on by auction and the precipitate washed with water. After re-= peated recrystallisation from 50% acetic acid the 4-nitro-4f-ureido diphenyl sulfide melts at 20 l 205 C. (uncorrected);

grs. of the same are then dissolved, while heating, in 800 cos. of glacial acetic acid. To this solution there are added 2 mols of 30% hydrogen peroxide solution and the reaction mixture heated on the steam bath. As soon as the reaction temperature has increased to about 0., there are added two more mols of hydrogen peroxide, thereby keeping the temperature at about 95 C. Thereafter the reaction mixture is continued'to be heated on the water bath for some time. Complete oxidation requires about 4 hours. On cooling 4-nitro-4'-ureido diphenyl sulfone crystallizes from the solution in a yield of about'70%. 0n recrystallisation from formic acid it shows a melting point of 225-226 C.

. mixture is poured into ice water.

tate is filtered off by suction and recrystallized times its volume of ice water.

purified by precipitating its solution in boiling Example 23 45 grs. of crude 4-nitro diphenyl sulfone-4"- carbaminic acid chloride are heated with 45 cos. of benzyl alcohol for 1 hours on the steam bath. Reaction takes place under lively development of hydrogen chloride gas. After the gas development has ceased the reaction mixture is cooled, filtered ofi, and the filtered residue recrystallized from glacial acetic acid. The 4-nitro-4'- carbaminobenzyloxy diphenyl sulfone, ob-

tained in a yield of 35-40 grs.,'has a melting point of 187-189 C.

Example 24 5.6 grs. of 4-amino-4'-nitrci diphenyl sulfone are dissolved in 25 cos. of dioxane, to this solution there are added 1.5 ccs. of pyridine and 3.5

grs. of chloro carbonic acid benzyl ester. Reaction takes place with simultaneous increase of temperature. After heating for about 30minutes on the water bath and cooling the reaction The precipifrom-glacial acetic acid. Yield: 4.0-4.5 grs. of

i-nitro-4-carbaminobenzyloxy diphenyl sulfone of M. P. 187-188 0.

Example 25 37.8 grs. of p-phthalamido-p-aminodiphenyl sulfone of M. P. 265 0., obtained by heating phthalic acid anhydride and p-amino-p -nitro diphenyl sulfone in glacial acetic acid, fusing the N-(p'-nitro diphenyl sulfone) -p-phthalaminic- 100 C. After addition of 320 grs. of ironturn- Example 28 e grs. of p-carbethoxyamino p nitro diphenyl sulfone, obtained, for instance, according to Example 12, are suspended in 3000 ccs. of formic acid. 200 cos. of hydrochloric acid are then added to thi suspension at 50 C. while stirring, and

thereupon under simultaneous heatingto 70 C. in small portions320' grs. of iron turnings which have been activated by means of concentrated hydrochloricacid. Hydrogen development takesplace, whereby the temperature increases to 95'- ings and 700 ccs. of concentrated hydrochloric acid the temperature of the reaction mixture is raised to 100 C., at ,which it i kept for 1 hour.v

After the-reaction is finished, the hot reaction mixture is filteredthrough asbestos and the'filtrate poured in times its amount of ice water.

The colourless precipitate is filtered oif by suction, washed with water and recrystallized from a mixture of equal parts of concentrated hydrochloric acid and water, to which 25% of its volume of formic acid was added. The yield of pcarbethoxy,-p'-amin o diphenyl sulfone of M. P. 229-230 C. obtained thereby, amounts to 230 Y .grs.=63%- of the theoretical yield.

. Example 29 chloride and 13.5 grs. of acetanili de are suspended in 150 ccsjof nitrobenzene and mixed with 26 acid of M. P. 191 C. at 200 -C.,,and reducing the p-phthalamido-p-nitro diphenyl sulfone of M. P.

255 C. by means of iron turnings'in formic acid in the presence of hydrochloric acid or by means of catalytically activated hydrogen in the pres' ence of nickel-catalyst according to Raney in absolute alcohol, are reacted in 100 ccs. of dioxane with a solution of 10 gm. of phosgene in dioxane according to Example 5. The carbaminic acid chloride obtained is reacted with concentrated ammonia as described in the same Example 5, whereby p-phthalamido-p'-ureidodiphenyl sulfone is obtained.

Example 26 N p'-amino diphenyl sulfone) -p-phtha1aminic acid, obtained either byreducing N(p-m'tro diphenyl-sulfone)-p-phtha1aminic acid by means of iron turnings and formic acid or by hydrolyzing p-phthalamido-p'-amirio diphenyl sulfone by means of 10% alcoholic potassium hydroxide solution, is reacted in dioxane in the presence of pyridine with chloro carbonic'acid ethyl ester at about 4050 C. with subsequent heating onv the steam bath, whereby N-(p'-carbethoxy amino diphenyl sulfone) -p phthalaminicacid is formed.

Example 27 95 grs. of N,N-bis-(4 '-nitro diphenyl su1- fone) -4-urea, obtained, for instance, according to Example 2, are suspended in 1000 cos. of formic acid and heated to 75 C., while stirring. 72 grs.

- of iron turnings and 382 ccs. of concentrated hydrochloric acid are added in small .portions.

After about 2 hours the hydrogen development ceases. The reaction mixture is then filtered through asbestos and the filtrate. poured in 10 The precipitate is alcohol with water. The bis-(4'-amino diphenyl sulfone) -4-urea of M. P. 236 C. is obtained in. a yield of 30 grs.

grs. of aluminum chloride in cos. of nitrobe'nzene. After heating for 1 hour at 120 -130 C. and cooling 1'5 ccs. of concentrated hydrochloric acid are addedand the nitrobenzene distilled off in a vacuum. 'The residue i -triturated with water and. filtered off from the undissolved product which is washed with water and-recrystallized from alcohol. It represents", the p-carbethoxyamino-p amlno diphenyl sulfone of M. P, 229

C. The acetyl group'of theacetanilide is split off j during the reaction;

Example 30 n 44 grspof p-carbethoxy amino benzene-sulfinic acid are boiled with 31.6 grs. of 2-chloro-5-riitr'o pyridine and 19.6 grs. of; potassium acetate in 1000 cos. of alcohol for 7 hours. The crystals preclpitated' are filtered 01f and recrystallized from glacial acetic acid. 40 grs. of p-carbethoxyamino pheny1p-nitro pyridyl sulfoneof M.- P. 195C. are obtained. on reducing the same in an analogous manner as described in-Examples 2; 3, 10, 12, 25, 26 and thelike p-carbethoxyamino phenylp'-amino pyridyl sulfone is obtained.

Example 31 9.2 grs. of p-carbethoxy amino benzene sulfinic acid aretgradually introduced-into 50 cos. of thionylchloride and the reaction mixture is heated for a short period of time on the water bath. On 1 cooling, p-carbethoxy amino benzene sulfinic acid chloride of M. P. 138 C. crystallizes. 70 grs. of

the same are added to 150 grs. of aniline and the mixture heated for about 60 minutes on the water bath. After cooling'the reaction mixture, is added to a mixtureof 2 N sodium hydroxide solution and ether. After shaking the layers are sepa-.

rated and the aqueous alkaline layer is filtered off bysuction. The residue is dissolved in 2 N hydrochloric acid solution and again precipitated with 2 N sodium hydroxide solution. Compact needles of p-carbethoxy amino-p"-amino diphenyl sulfoxide are obtained, 20- gm. of which are boiled in about ccs. of acetic acid anhydride 26.3 grs. of p-carbethoxy' amino benzene sulfo I asaeeee for 15 minutes. 'Ihereupon the reaction mixture is mixed on the water bath with alcohol until the excess of acetic acid anhydride is destroyed. On

cooling p-carbethoxy amino-p-acetyl amino diphenyl sulfoxide crystallizes in fine colourless needles of M. P. 274 C.

100 grs. of the same are oxidized in about 50 cos. of glacial acetic acid with 5% aqueous ptassium permanganate solution. On cooling pcarbethoxy amino-p'-acetyl amino diphenyl sul- 'Ihepartia'l saponification may also be carried out by boiling in a mixture of 8 parts ofalcohol and 2 parts of concentrated hydrochloric acid, where, however, 2 hours are required for completi'n'g the reaction.

Example 32 26 grs. of p-carbethoxyamino pyridine sulfochloride in 100 cos. of nitrobenzene are mixed with 13.5 grs. of acetanilide and 30 grs. of aluminum chloride in 50 cos. of nitrobenzene are added in small portions to the reaction mixture. Afterheating for aboutl hour at 120 C... distilling oil the nitrobenzene, and adding about 15 cos. of concentrated hydrochloric acid and 100 cos. of water, the residue is filtered off bysuction and washed with a. large amount of water. ethoxyamino pyridyl) -4'-amino phenyl sulfone is obtained.

Example 33 5.6 grs. of 2-amino pyridine-5-sulfonicv acid are intimately mixed with 2.75 grs. of sodium bicarbonate and a small amount of water. After heating for a short period of time the reaction mixture is evaporated to dryness in a vacuum and dried at 200 C. in a vacuum. 'Iher'eupon it is mixed with double its amount of acetic acid anhydride and boiled for 1. hour under reflux. After cooling the excess acetic acid anhydride is destroyed by means of alcohol on the water bath and mixed with the same volume of water. cooling crystals of the sodium salt of Z-acetylamino pyridine-5-sulfonic acid are obtained which are transformed into the'free acid of M. P. 360 C. by precipitation of their aqueous solution with concentratedhydrochloric acid.

grs. of the absolutely dry potassium salt of the 2-acetylamino pyridine-5-sulfonio acid are heated in a sealed glass tube with phosphorus pentachloride to 160 C. On reducing thesulfochloride with sodium sulfite in weakly alkaline solution in an analogous manner as is known for p-carbethoxy amino benzene sulfochloride, the corresponding sulflnic acid is obtained.

. 50 grs. oi 2-acetyl amino pyridine-5-sulfinic acid are boiled with 49.7 grs. of 2-chloro-5-nitro pyridine and 24.9 grs. of potassium acetate in 1000 cos. of alcohol for 8 hours under reflux. On cooling crystals of 2-acetylarnino-2-nitro dipyridyl-5,5-sulfone are obtained which on reduction, as described above, for instance, ac-

5,5 -sulf one.

Eazample 34 208 grs. of l-carbethoxybenzene sulfinic acid are heated with 389 grs. of methylaniline for 8 Thus, 4-(2-carbhours on the steam bath. The crystal paste forming in the beginning dissolves in the course of 2-3 hours. more deeply violet and drops of water separate.

After cooling and standing for a longer period of time, the content of the reaction container solidifies to a crystal paste which is filtered off by suction and washed on the filter first with acetic acid esterand then with ether. 3 The 4- monomethyl 4 carbethoxy @A' diamino diphenyl sulfoxide still shows a slight violet colour and has a melting point of 174-175 C. after recrystallisation flrst from acetic acid ester and then from methanol. It is readily soluble in alcohol, methanol, acetone, chloroform, dinicultly soluble in hot acetic acid ester, and insoluble in water and petrol ether. Yield: 157 grs.=5'1' .5%. 15,7 grs. of this compound are heated with 285 cos. of acetic acid anhydride for 1 hour on the steam bath. After coolingto room temperature a solution of 55 grs. of chromium trioxide (1.1 mol) in 25 cos. of water and 200 cos. of

glacial acetic acid are added while stirring whereby care is taken that the temperature in the reaction mixture does not rise above 80 C. After addition of the oxidizing solution the reaction mixtureis heated for minutes on the which shortly becomes crystalline.

steam bath. After cooling it is then poured slowly into 10 liters of ice water whereby the 4- monomethyl acetyl--carbethoxy-4,4-diarnino diphenyl sulfone' precipitates first in syrupy form 162 grs. are obtained=87 On recrystallisation from methanol the compound shows a. melting point of 187 C. It is readily soluble in alcohol, acetone, chloroform, hot acetic acid ester and acetic acid, diiiioultly soluble in benzene, insoluble in Water and petrol ether.

grs. of l-monomethyl acetyl-dI-carbethoxy- 4,4'-diamino diphenyl sulfone are heated with a solution of 250 cos. of concentrated hydrochloric acid and 750 cos. of alcohol for 2 hours under reflux. Thereafter the solution is concentrated by evaporation in a vacuum to 300 ccs. and

poured into 3 liters of ice water, whereby l-mono methyl 4-carbethoxy 4,4 diamino diphenyl sulfone precipitates in crystalline form. Yield 41.5 g'rs.==93%. The product is recrystallized first from glacial acetic acid and then from methanol and melts at 212-213 C. .It is readily soluble in acetone, hot dioxane and alcohol, insoluble in water, ether, petrol ether. I

Example 35 17.4 grsfof i-ureido-4-arnino 'diphenyl sulfone are dissolved in 200' cos. of acetone, to which 5.7 cos. of pyridine are added. While stirring, then 5.7 cos. of chlorocarbonic acidethyl ester are introduced, whereby the temperature of the reaction mixture increases to et 50 C. After allowing the reaction solution tostand for sev- Example 36 10 grs. of 4,4'-diamino diphenyl sulfone are dissolved in 25 cos. of acetone, to which 6.4 grs.

of pyridine are added. Into this solution 6.3 grs.

of chlorocarbonicacid ethyl ester are introduced The solution becomes more and The 4- from pyridine. M. P. 256 C. (thereby decomposing). Yield: 'Igrs.

Of course, many changes and variations in the reaction conditions, the starting materials used, the solvents and catalysts employed, the reaction temperature and duration, the methods of isolating and purifying the final products and so forth may be employed by those skilled in the art in accordance with the principles set forth herein and in the claim annexed hereto What we claim is: A p,p-diphenyl sul'lone derivative of the for- MAX DGHRN.

WAL'IER SCI-IOELLER. o'rro LAUBEREAU. HERMANN FOX. ERICH LECKZYCK. HANS HERLOFF' INHOFFEN. 

